ABSTRACT
The early phase of drug development is concerned with determining the safe and effective dose to give patients in future clinical trials. In this carefully planned phase very low doses of an active drug are given to a small number of healthy human volunteers to determine the pharmacokinetics (PK) of the drug. Assuming an orally administered drug is being studied, PK is concerned with obtaining information on the absorption, distribution, metabolism and elimination of the drug. Quite often PK is referred to as ‘what the body does to the drug’. An important outcome of a PK study is an assessment of how much of the active constituents of the drug reaches its site of action. As this cannot be easily measured directly, the concentration of drug that reaches the circulating bloodstream is taken as a surrogate. The concentration of drug that is in the blood is referred to as its bioavailability. It is assumed that a drug with a larger bioavailability than another will also be such that a greater amount of its active ingredients reach the intended site of action. Two drugs which have the same bioavailability are termed bioequivalent. (See Food and Drug Administration (FDA) Guidance, 1992, 1997, 1999b, 2000, 2002.) Statistical approaches to determining bioequivalence are described in FDA Guidance (1992, 1997, 1999a, 2001). There are a number of reasons why trials are undertaken to show two drugs are bioequivalent. Among them are (1) when different formulations of the same drug are to be marketed, for instance in solid tablet or liquid capsule form; (2) when a generic version of an innovator drug is to be marketed, (3) when production of a drug is scaled up and the new production process needs to be shown to produce drugs of equivalent strength and effectiveness to the original process. In all of these situations there is a regulatory requirement to show that the new or alternative version of the drug is bioequivalent to what is considered to be its original version.
